On this page
Hereditary angioedema type III
This condition typically affects the skin, gastrointestinal tract, and airways, leading to unpredictable and sometimes severe swelling. It is an inherited disorder, meaning it can be passed down through families.
Overview
Hereditary angioedema type III (HAE type III) is a rare inherited condition characterised by recurrent bouts of swelling (angioedema). Unlike some other forms of angioedema, HAE type III typically occurs without hives (urticaria). The swelling can affect various parts of the body, including the skin, the lining of the digestive system, and the airways [PMID:33675003]. These episodes can be unpredictable and range in severity.
Symptoms & clinical features
The main symptom of HAE type III is swelling that develops suddenly and can last for several days. This swelling can affect many different parts of the body. When it occurs under the skin, it often appears on the face, lips, hands, feet, or genitals. Swelling of the gastrointestinal tract can lead to severe abdominal pain, nausea, vomiting, and diarrhoea, which may sometimes be mistaken for other acute abdominal conditions. The most dangerous symptom is swelling in the upper airway, as this can obstruct breathing and become life-threatening [PMID:33675003]. Unlike allergic reactions, HAE type III swelling does not usually itch or respond to antihistamines.
Video: Genetics 101
Affected organs
HAE type III primarily affects tissues where fluid can accumulate, leading to swelling. The skin is a common site, with oedema often seen on the face, extremities, and genitals. The mucous membranes of the gastrointestinal tract are also frequently involved, causing abdominal pain and other digestive symptoms. Critically, the upper airways, including the larynx (voice box), can swell, posing a risk of airway obstruction [PMID:24606227].
Risks & severity
The severity of HAE type III symptoms can vary significantly between individuals, even within the same family. Swelling episodes can be triggered by stress, trauma, hormonal changes (such as those associated with pregnancy or oestrogen-containing medications), or sometimes occur without an obvious trigger. Airway swelling is the most serious complication and requires urgent medical attention. Although HAE type III is generally considered a rare condition, the exact prevalence is not well established.
Genetic causes
HAE type III is associated with pathogenic variants in the F12 gene. This gene provides instructions for making coagulation factor XII, also known as Hageman factor. Factor XII plays a role in blood clotting and inflammation pathways [PMID:24606227]. Normally, factor XII helps regulate processes that lead to the production of bradykinin, a molecule that increases blood vessel permeability and can cause swelling. Pathogenic changes in F12 are thought to lead to an overproduction or reduced breakdown of bradykinin, resulting in uncontrolled swelling episodes [PMID:33675003].
- F12 coagulation factor XII
Inheritance pattern
Hereditary angioedema type III follows an autosomal dominant inheritance pattern. This means that an individual only needs to inherit one copy of the altered F12 gene from one parent to develop the condition. If a parent has HAE type III, each of their children has a 50% chance of inheriting the pathogenic variant and therefore the condition. The condition affects males and females equally, although symptoms may sometimes be more pronounced or triggered differently in females, often linked to oestrogen levels.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of HAE type III typically involves a combination of clinical assessment and genetic testing. A doctor will consider the patient's symptoms, particularly recurrent episodes of non-itchy swelling without hives. Genetic testing to identify pathogenic variants in the F12 gene can confirm the diagnosis. In the UK, genetic testing for inherited angioedema is available through the NHS Genomic Medicine Service, often following a referral from a specialist clinic. The relevant R-code for hereditary angioedema genetic testing would be requested by a clinical genetics service or a specialist immunology team.
Management & lifestyle
Management of HAE type III focuses on preventing swelling attacks and treating them promptly when they occur. This may involve avoiding known triggers where possible. Specific medications are available to treat acute attacks, and some individuals may benefit from long-term preventative therapies, particularly if their attacks are frequent or severe. Treatment approaches are individualised and should be discussed with a specialist. Patients with HAE type III should carry an emergency plan and communicate their condition to all healthcare providers. Management decisions are made in consultation with a clinical immunologist or a specialist in inherited angioedema, aligned with NHS clinical guidelines.
UK care pathway
In the UK, individuals suspected of having hereditary angioedema type III would typically be referred to a specialist, such as a clinical immunologist. If genetic testing is indicated, this would be arranged through the NHS Genomic Medicine Service, often following a referral to a clinical genetics department. Genetic counsellors play a vital role in explaining the genetic basis of the condition, inheritance patterns, and implications for family members. The testing falls under the national Genomic Medicine Service 'R-codes' for rare and inherited diseases.
Frequently asked questions
What triggers HAE type III attacks?
Swelling attacks in HAE type III can be triggered by various factors, including physical trauma, stress, infections, and certain medications, especially those containing oestrogen. Sometimes, no specific trigger can be identified before an attack.
Is HAE type III curable?
Currently, there is no cure for HAE type III. However, treatments are available to manage symptoms, prevent attacks, and reduce their severity, significantly improving the quality of life for affected individuals.
How does HAE type III differ from allergic reactions?
HAE type III swelling is typically not itchy and does not involve hives (urticaria), unlike most allergic reactions. It also does not respond to antihistamines or adrenaline, which are commonly used for allergic reactions.
Can HAE type III affect my children?
Yes, because HAE type III is an autosomal dominant condition, if you have the condition, each of your children has a 50% chance of inheriting the pathogenic F12 variant and therefore the condition.
What should I do during an HAE type III attack?
It is important to follow the emergency plan provided by your specialist. This typically involves administering specific medications to stop the swelling. If airway swelling occurs, seek immediate emergency medical care.
References
- LoVerde D, Files DC, Krishnaswamy G. Angioedema. Critical care medicine. 2017. PMID: 28291095
- Naudin C, Burillo E, Blankenberg S. Factor XII Contact Activation. Seminars in thrombosis and hemostasis. 2017. PMID: 28346966
- Miranda AR, Ue AP, Sabbag DV. Hereditary angioedema type III (estrogen-dependent) report of three cases and literature review. Anais brasileiros de dermatologia. 2013. PMID: 24068129
- Napolitano M, Vastarella M, Fabbrocini G. Hereditary angioedema type III, recurrent pregnancy loss and heterozygous MTHFR mutation. Dermatologic therapy. 2020. PMID: 33188583
- Bork K. Hereditary angioedema with normal C1 inhibitor. Immunology and allergy clinics of North America. 2013. PMID: 24176211
- Björkqvist J, de Maat S, Lewandrowski U. Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III. The Journal of clinical investigation. 2015. PMID: 26193639
- Bork K, Wulff K, Witzke G. Treatment for hereditary angioedema with normal C1-INH and specific mutations in the F12 gene (HAE-FXII). Allergy. 2017. PMID: 27905115
- Cichon S, Martin L, Hennies HC. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. American journal of human genetics. 2006. PMID: 17186468